6-(5-membered heteroaryl)isoquinolin-3-yl-(5-membered heteroaryl) carboxamides and preparation and use thereof

1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-3 haloalkyl), and unsubstituted —(C 1-3 alkyl);

R 3 is a 5-membered heteroaryl optionally substituted with 1-4 R 36 ;

R 6 is selected from the group consisting of —(CH 2 )(5-membered heteroaryl) optionally substituted with 1-4 R 37 and 5-membered heteroaryl optionally substituted with 1-4 R 38 ;

with the proviso that R 6 is not

each R 36 is independently selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 44 , and -carbocyclyl optionally substituted with 1-12 R 45 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

alternatively, two adjacent R 36 taken together form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 46 and -carbocyclyl optionally substituted with 1-12 R 47 ;

each R 37 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 39 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 40 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 38 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 39 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 40 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 39 is independently selected from the group consisting of unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —C(═O)O(R 41 ), —N(R 42 ) 2 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 43 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 40 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —CN;

R 41 is selected from the group consisting of unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

each R 42 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

each R 43 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —CN;

each R 44 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 43 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 45 independently is selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 43 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 46 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 43 ; wherein-(C 1-4 alkylene) is, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 47 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —CN; and

each p is independently 0 or 1.

2. The compound of claim 1 , wherein R 1 , R 2 , R 4 , and R 5 are H.

3. The compound of claim 2 , wherein R 3 is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, and oxazolyl, each optionally substituted with 1-4 R 36 .

4. The compound of claim 3 , wherein R 3 is selected from the group consisting of pyrazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, thiadiazol-2-yl, and oxazol-5-yl, each optionally substituted with 1-4 R 36 .

5. The compound of claim 4 , wherein R 3 is a pyrazol-4-yl substituted with one —(C 1-3 alkyl).

6. The compound of claim 4 , wherein R 3 is a imidazol-5-yl substituted with one —(C 1-3 alkyl).

7. The compound of claim 4 , wherein R 3 is a imidazol-5-yl substituted with two —(C 1-3 alkyl).

8. The compound of claim 4 , wherein R 3 is a 1,2,3-triazol-4-yl substituted with one —(C 1-3 alkyl).

9. The compound of claim 4 , wherein R 3 is an unsubstituted thiadiazol-2-yl.

10. The compound of claim 9 , wherein R 3 is a thiadiazol-2-yl substituted with one —(C 1-3 alkyl).

11. The compound of claim 4 , wherein R 3 is an unsubstituted oxazol-5-yl.

12. The compound of claim 11 , wherein R 3 is a oxazol-5-yl substituted with one —(C 1-3 alkyl).

13. The compound of claim 4 , wherein R 6 is —(CH 2 )(5-membered heteroaryl) optionally substituted with 1-4 R 37 .

14. The compound of claim 4 , wherein R 6 is 5-membered heteroaryl optionally substituted with 1-4 R 38 .

15. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method of treating a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of: chronic inflammation, systemic inflammation, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological condition/disorder/disease, osteoarthritis, lung disease, a fibrotic disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutical composition, wherein the patient is a human.

18. The method of claim 17 , wherein the cancer is selected from the group consisting of: osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, and gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors, neurofibroma, meningioma, glioma, and sarcoma.

19. The method of claim 17 , wherein the disorder or disease is a neurological condition/disorder/disease, wherein the neurological condition/disorder/disease is selected from the group consisting of: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND), FTD amyotrophic lateral sclerosis, also called FTD-ALS, corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), Prion Diseases, globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, lewy body dementia, Parkinson's disease, Pick's disease, autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; chronic traumatic encephalopathy, traumatic brain injury, tumor, stroke, frontotemporal dementias, dementia with lewy bodies, prion diseases, multiple system atrophy, inclusion body myositis, degenerative myopathies, diabetic neuropathy, metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, and Charcot-Marie-Tooth disease.

20. The method of claim 17 , wherein the disorder or disease is a neurological condition/disorder/disease associated with tau protein, amyloid, alpha-synuclein, Tar DNA-binding Protein of 43 KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS) pathology.

21. The method of claim 17 , wherein the disorder or disease is a fibrotic disorder, wherein the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease, and radiation fibrosis.

22. The method of claim 17 , wherein the disorder or disease is chronic inflammation associated eye disorders, joint pain, arthritis: rheumatoid arthritis, osteo arthritis, psoriatic gout; cancers: colon cancer, breast cancer, lung cancer, pancreatic cancer; gastrointestinal disorders: ulcerative colitis, inflammatory bowel diseases; pulmonary disorders; allergies, skin disorders; diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, neurological disorders: multiple sclerosis, Parkinson's, dementia and Alzheimer's disease.

23. A method of preventing or reducing angiogenesis in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.